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Von Willebrand Disease

Bild: “Epitaxis” von Welleschik. Lizenz: CC BY-SA 3.0


Definition and Epidemiology of von Willebrand Disease

Increased bleeding tendency: von Willebrand disease

Von Willebrand Disease

Image: “Epitaxis” by Welleschik. License: CC BY-SA 3.0

Von Willebrand disease (VWD) is named after the Finnish physician, Erik von Willebrand. He examined a family that was living on the Aaland Islands in the Baltic Sea who regularly experienced severe bleeding. He jokingly called the island “Nose Bleed Island”.

He summarized the conclusions of his examination, creating a new clinical picture he called “pseudohemophilia”; thus, differentiating it from hemophilia. Over the years, this condition became known as “von Willebrand disease”.

VWD is the most commonly inherited disorder of hemostasis and has a relatively high prevalence (1:100). Men and women are equally affected. The disease is caused by a qualitative or quantitative deficiency in the von Willebrand factor (VWF) with various clinical manifestations. In order to understand the concept of this hemorrhagic diathesis, it is important to understand the function of VWF.

Pathophysiology of von Willebrand Disease

Human von Willebrand Factor

Image: “Human von Willebrand Factor” by Nevit Dilman. License: CC BY-SA 3.0

VWF is a glycoprotein that is produced in the endothelium and megakaryocytes, and is located in the so-called Weibel-Palade bodies as a multimer. It is involved in various hemostatic processes:

During primary hemostasis, VWF binds to the proteins of the subendothelial matrix and to the surface of platelets. This creates an adhesive connection between the endothelium and platelets. Glycoprotein Ib/IX on the surface of platelets plays an important role here.

As a result of the adhesion to the platelets, VWF activates platelet functions that result in platelet aggregation.

VWF forms a complex with clotting factor VIII in order to prevent its proteolytic degradation. This notably extends the half-life of factor VIII and preserves its functions.

VWF is also an acute-phase protein that is increasingly synthesized and secreted during inflammatory processes. It spontaneously transforms into multimers in the plasma. These multimers are proteolytically degraded by the protease ADAMTS13 which plays an important role in thrombotic microangiopathy and the hemolytic-uremic syndrome among others.

Proteolytic processing of von Willebrand factor by adamts13 and leukocyte proteases.

Image: “Proteolytic processing of von Willebrand factor by adamts13 and leukocyte proteases.” by Openi. License: CC BY 2.0

Etiology of von Willebrand Disease

Classification of the von Willebrand disease

Many forms of vWD are hereditary:

 Type 1  Autosomal dominant  75 % of patients, varies mild to severe
 Type 2A  Autosomal dominant  15 % of disease, moderate
 Type 2B  Autosomal dominant  5 % of disease, moderate
Platelets-Type  Extremely rare  “Gain of function” mutation results in hypercoagulability rather than bleeding
 Type 2M  Rare  Normal level of vWF, but abnormal binding
 Type 2N  Autosomal recessive  Low factor 8, mistaken for hemophilia in boys
 Type 3  Very rare  Unmeasurable vWF, low factor VIII

Apart from this, there are many forms of VWD that result from other underlying diseases. In particular, hemato-oncological diseases, which are accompanied by increased antibody production, can cause VWD. Such diseases include monoclonal gammopathies, malignant lymphomas, and autoimmune or myeloproliferative diseases.

Von Willebrand disease and aortic valve stenosis

A rare but interesting phenomenon is the frequent coincidence of symptomatic VWD in the course of an aortic valve stenosis. This coincidence is called Heyde’s syndrome and is not fully understood. It is assumed that plasma VWF forms multimeric clews as described above. This formation impedes proteolytic degradation by ADAMTS13.

When the multimer flows through the stenotic aortic valve, the resulting mechanical stress forces it to unroll. ADAMTS13 can now perform increased proteolytic degradation and the valve size reduces, thus, impairing VWF function. The VWF multimer is inactive when degraded and is unable to perform its function in defective peripheral blood vessels. The result is VWD.

The pathophysiology of acquired von Willebrand’s Disease type 2A (vWD-2A) from an aortic stenosis (Heyde’s Syndrome)

Image: “The pathophysiology of acquired von Willebrand’s Disease type 2A (vWD-2A) from an aortic stenosis (Heyde’s Syndrome).” by Michael D. Dacre. Lizenz: CC BY-SA 4.0

Note: The opposite mechanism occurs during hemolytic-uremic syndrome and thrombotic microangiopathy. A lack of ADAMTS13 causes the decreased degradation of VWF multimers. This results in the formation of platelet-rich thrombi with microangiopathy (particularly in the kidneys and brain) and consumption thrombocytopenia. This example clearly reflects the principle of balance in hemostasis. Lack of balance in such a complex system can rapidly cause increased bleeding on one hand and formation of thrombi on the other hand.

Clinical Picture of von Willebrand Disease

Symptoms of von Willebrand disease

petechiae

Image: “petechiae” by Peter Rammstein. License: CC BY 3.0

Although the function of VWF is very complex and integrates various processes, most patients do not complain about symptoms or are affected by mild symptoms alone.

The clinical picture, as described above, depends on the particular disease type. Thrombocytic and hemophilic bleeding types are predominant when pathological bleeding occurs (pursuant to the pathophysiology). Mucosal bleeding is typically reported. Often, the patient is unaware of the increased bleeding tendency until increased peri- or postoperative bleeding occurs.

Signs and symptoms are:

 Easy bruising
  • Spontaneous
  • Large
  • Unusual locations
 Skin bleeding
  • Minor lacerations with prolonged bleeding
  • Excessive scarring
 Nose/mouth
  • Frequent nosebleeds
  • Hard to control nosebleeds
  • Bleeding with tooth loss
  • Bleeding after brushing
 Menorrhagia
  • Increased bleeding with menses
  • Longer menses

Diagnosis of von Willebrand Disease

Genetic diagnostics of von Willebrand disease

Because of its mostly genetic origin, a detailed family medical history is pertinent. Note that in mild forms, VWD often remains undetected. The clinical bleeding type can lead to the discovery of where in the hematologic system this particular pathology is located. Laboratory results usually show a prolonged bleeding time, possibly a prolongation of APTT and a deficiency of factor VIII. However, VWD cannot be ruled out if APTT and factor VIII levels are normal.

A special VWD diagnosis is indicated when there is reasonable suspicion. Definitive testing:

  • vWF antigen
  • Ristocetin cofactor activity
  • Factor VIII level (will be different in different subtypes of disease)

Treatment of von Willebrand Disease

Therapeutic options of von Willebrand disease

Patients should, like in all cases of hemorrhagic diathesis, receive daily prophylaxis. If bleeding occurs or if an operation is required, it is essential to stop the bleeding completely. Acetylsalicylic acid and other antiplatelet drugs are contraindicated.

There are several options for pharmaceutic treatment:

structural formula desmopressin

structural formula desmopressin

Minor bleeding can be treated with desmopressin (analog of ADH (DDAVP)). It binds to V2 receptors and stimulates the release of VWF from the Weibel-Palade bodies. The effect of this release begins to work within 30–60 minutes and continues for several hours, so as to stop the bleeding. The effect of this medication depletes over time, therefore, its administration is limited. Desmopressin can be administered as nasal sprays or pills. Nasal sprays are a particularly good everyday option for affected children.

  • If heavy bleeding occurs, especially peri- or postoperatively, replacement therapy is required. Planned replacements are advised in cases where bleeding is expected to occur. For such cases, concentrates that contain factor VIII and VWF can be given.
  • Affected women can take oral contraceptives in order to reduce their menstrual bleeding and thus prevent notable blood loss.
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